Amino pyrimidines



Patented Nov. 29, 1949 UNITED STATES i rtTENT OFFICE AMINO PYRIMIDINESAlbert Frederick Crowther, Francis Henry Swinden Curd, Barbara JeanLovell, and Harry Tacon Openshaw,

Manchester, and Alexander Robertus. Todd, Cambridge, England, assignorsto Imperial Chemical Industries Limited, a corporation of Great Britainrial No. 708,436. 12, 1945 5 Claims.

RR N-k-NW-(l -Y NONH2 wherein X is hydrogen or a hydrocarbon radical, Yis hydrogen or a neutral substituent, and also X and, Y may togetherform a. single alkylene chain, R" is hydrogen or an alkyl or simply substituted alkyl group, for example, an alkoxyalkyl or dialkylaminoalkylgroup, A is a linking group which is aliphatic or alicyclic oraliphaticc'arbocyclic and may be substituted, for example,

by hydroxy,

with a di'amine NI-lR"A:-NRR', the various symbols in these formulaehaving the same meanings as before and Z representing a labile groupsuch as a halogen atom, or; a hydrocarbon radical which is attached bymeans of an ether, or thioether linkage, for example, an alkoxy, aryloxyor alkylmercapto group.

The reaction isconveniently brought about by heating the reagentstogether, optionally in the presence of a solvent or diluent. The tworeagentsv may both be used as free bases, or, if desired, theaminopyrimidine derivative may be used as the free base and. the diaminein th form of a salt, for instance the hydrochloride, or acetate, or thediamine may be used as free base and the aminopyrimidine derivative as asalt. Also if desired the reaction may be carried out in the presence ofan acid-binding agent such as sodium hydroxide.

The reagents. are conveniently, ut n t n s- Drawing. ApplicationNovember 7, 1946,, Se-

In Great Britain November sarily used in approximately stoichiometricproportions. If desired alarge excess of the diamine may be used so thatit functions as a solvent; indeed with they diprimary diamines it ispreferable to work in this way.

It will be appreciated that where it is. desired to introduce asubstituent of the form (B. being hydrogen or a hydrocarbon radical) itwill usually be necessary first to protect the amino. group NI-IR, as byacylation, and then to remove the protecting group after thecondensation with the aminopyrimidine compound has been effected. Thisprocedure is, in fact, a particular embodiment of one of the modifiedprocedures now to be described.

A further feature of the invention is a modified process wherein thebasic substituent -l TR-A-NRR' is introduced by stages. Thus theZ-aminopyrimidine derivative carrying a labile group in the 4-positionis brought into reaction with an amino compound of the formula NHR-A'B,where A represents either the whole or part of the linking group definedabove and where B stands for a reactive group which is then converteddirectly or indirectly by methods involving the step of reaction witharmmonia or a compound containing an amino group into the group NRR' orinto a group -A--NRR' such that A and A together constitute the linkinggroup A. For example, the group B may be a hydroxy group or a derivativethereof which is, or is readily convertible to, a reactive esterthereof, such as a halide, this then being brought into reaction with anamine NHRR' or an amino substituted amine NH2-A" '-NRR/ or a hydrcxy ormercapto. substituted amine group such as piperidino or by bringing itinto reaction with a halogeno-substituted amine Hale-A" NRR' such thatA'--NH-A" constitutes the linking group A.

Of the aminopyrimidine derivatives required as starting materials2-ethylmercapto-4-amino-5- methylpyrimidine is known, having been madeby reaction of ammonia with the corresponding e-chloro compound, itselfobtained by chlorination of the hydroxy derivative, made by interactionof S-ethyl isothiourea with ethyl formylpropionate (see AmericanChemical J ournal, 1904, vol. 31, p. 591).Z-methylmercapto-lamino-:G-dimethylpyrimidine (B. P. 158-159.5 C.) issimilarly made by reaction of ammonia in ethanol at 115-125 C. for 6hours with the 4- chloro compound (M. P. 35-36 C.) itself obtained byreaction of phosphorus oxychloride on 2-methylmercapto-4-hydroxy-5o-dimethylpyrimidine (for which see J. Amer. Chem. Soc., 1936, vol. 58,p. 769). 2-chloro-4-amino-6- methylpyrimidine is likewise known, havingbeen made by fractionation of the product of reaction of ammonia inethanol on 2z-dichloro- G-methylpyrimidine (see Berichte, 1-309, vol.32, p. 2923). Other analogous starting materials suitable for use in thepresent invention may be made by methods essentially similar to thosejust described.

The following examples serve to illustrate the practice of theinvention. The parts are by weight.

Eramplei 5.6 parts of 4-amino-2-methylmercapto-5:6- dimethylpyrimidineand 8.6 parts of 'y-diethylaminopropylamine are heated together in anautoclave at 200-210 C. for 22 hours. The excess of the amine is thendistilled off under diminished pressure and the residue is dis-tilled at5 10 mm. from a bath at 170-175 C. The distillate contains the desiredproduct accompanied by a small amount of unchanged starting material.Repeated distillation under the same conditions, rejecting the lowerboiling fractions, eliminates the unwanted starting material and i-amino2 'y diethylaminopropylamino 5:6- dimethylpyrimidine is obtained as apale yellow oil. It forms a his 3:5-dinitrobenzoate which crystallisesfrom ethanol in pale yellow prisms of M. P. 210-212 C.

The 4-amino-2-methylmercapto-5 S-dimethylpyrimidine required as startingmaterial is made by interaction of ammonia in ethanol for 6 hours at115-l25 C. with 4-chloro-2-methylmercapto- 5:6-dimethylpyrimidine (M. P.35-36 C.), itself made by reaction of phosphorus oxychloride with thecorresponding 4-hydroxy compound (for which see J. Amer. Chem. Soc.,1936, vol. 58, p. 769).

Example 2 Example 3 4 parts of 2 chloro-4-amino-fi-methylpyrimidine andparts of B-diethylamino ethylamine are heated together under reflux forsix hours. There are then added 400 parts of water and a sufiiciency ofsodium hydroxide solution to The exmake the mixture definitely alkalineand the unchanged diamine is distilled off in steam. The residue isacidified with concentrated hydrochloric acid and the solution isclarified with charcoal and filtered. The filtrate is made alkaline withsodium hydroxide and the base which separates as an oil is extractedwith benzene. The benzene solution is dried and the solvent is distilledofi. The residue solidifies on cooling and is crystallised from amixture of benzene and petroleum ether (B. P. (SO- C.). There is thusobtained Z-p-diethylamino ethylamino-l-aminoo-methylpyrimidine of M. P.-101 C.

Example 4 10 parts of 2-chloro-4-amino-G-methylpyrimidine and 50 partsof fi-diethylamino-a-methylbutylamlne are boiled together under refluxfor six hours. The mixture is then worked up as described in Example 3.The residue after removal of the benzene is distilled under diminishedpressure whereby -amino 2 c-diethylamino-emethylbutylamino 6methylpyrimidine is obtained as an oil of B. P. l52-156 C. at 0.17 mm.It forms a dipicrate which crystallises from a mixture of ethanol andp-ethoxyethanol with M. P. 138-139 C.

Example 5 a parts of 2ch1oro-4-amino-6-methylpyrimidine and 20 parts of'y diethylaminopropylamine are refluxed together for five hours. Theexcess of the diamine is then distilled ofi under diminished pressureand the oil which remains is dissolved in dilute hydrochloric acid. Thesolution is made alkaline by addition of caustic soda and the oil whichis precipitated is extracted with benzene. The benzene solution is driedand the solvent is distilled ofi. The oil which remains is distilled inhigh vacuum. There is thus obtained l-amino-Z 7 dlethylaminopropylamino-G-methylpyrimidine which is a pale yellow viscous oil. It forms a bis3:5-dimtrobenzoate which crystallises from ethanol in pale yellow prismsM. P. 218-220 C.

Example 6 5 parts of 2-chloro-4-amino-S-methylpyrimidine and 20 parts of'y-dibutylarnino propylamine are heated together at ISO- C. for sixhours. The excess of diamine is then distilled off under diminishedpressure and the oil which remains is dissolved in dilute hydrochloricacid. The solution is made alkaline with sodium hydroxide and the oilwhich is precipitated is extracted with ether. The ether solution isdried and the solvent is distilled ofi. The oil which remains isdistilled at 15x10" mm. from a bath at 200- 210 C. There is thusobtained 4-amino-2- -dibutylaminopropylamino B-methylpyrimidine in theform of a yellow oil. The bis 3:5-dinitrobenzoate crystallises fromethanol in pale yellow prisms, M. P. ZOO-202 C. with charring.

Example 7 2 parts of 4 amino 2 methylmercapto 6 methylpyrimidine and 2.6parts of -y-dimethylaminopropylamine are heated together in an autoclaveat 160-170 C. for 14 hours. The product is treated in the same way as isthat of Example 1 and 4 amino 2 'y dimethylamino propylamino 6methylpyrimidine is obtained as a pale yellow viscous oil, B. P. 180-200C. (bath temperature)/l0- mm., which does not crystallise. The bis 3:5dinitrobenzoate crystallises 5 from alcohol in pale yellow hygroscopicneedles, M. P. 223-225 C.

We claim: 1. As new compounds, the pyrimidine derivatives of the formulaN=CX RRN-A-NJEP-(J LY N-(-NH:

wherein R and R are alkyl radicals of 1 to 4 carbon atoms each, A is ahydrocarbon linking group of not more than 3 carbon atoms, X is a loweralkyl radical and Y is a member selected from the group consisting ofhydrogen and lower alkyl radicals.

2. As new compounds, the pyrimidine derivatives of the formula N=C-CH:

RRN-A-NH- H wherein R and R. are alkyl radicals of 2 to 4 carbon atomseach, while A is a hydrocarbon linking group of not more than 3 carbonatoms.

REFERENCES CITED The following references are of record in the file ofthis patent:

Survey of Antimalarial Drugs 1941-1945, by Frederick Wiselogle.

J. W. Edwards, Ann Arbor, Mich. (1946), Volume 2, part 2, pages 1426 and1427.

Journal of the American Chemical Society, vol. 67 (1945) pages1159-1161.

Chemical Abstracts, vol. 35, page 5791*.

